Dispensing device (cat)

ABSTRACT

A dispensing device, a storage device and a method are proposed for dispensing a formulation as a spray. The formulation is dispensed by means of a gas stream. To improve the dispensing effect, pressure pulses are generated in the gas stream and/or the direction of gas flow alternates. The formulation is dispensed through a duct. The duct is connected to a storage chamber containing the formulation via a sharp edge or transition portion.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to a dispensing device for dispensing apreferably medical formulation, in particular containing or consistingof a drug or mixture of drugs as a spray, to a storage device for apreferably medical formulation, in particular, containing or consistingof a drug or mixture of drugs, and to a method for dispensing such aformulation as a spray.

2. Description of Related Art

Drugs delivered through dispensing devices, in particular inhalers, areintended to optimally target specific sites in the pulmonary system.These sites include the nasal passages, the throat, and variouslocations within the lungs, such as the bronchi, bronchioles andalveolar regions. The ability to deliver drugs to a target area dependsinter alia on the aerodynamic sizes of the particles or droplets. Ascurrently believed to be understood, particles having an aerodynamicdiameter of less than 2 micrometer are considered to be potentiallyoptimal for deposition in the alveolar region of the lung. Particlesthat have an aerodynamic diameter of between 2 and approximately 5micrometer may be more suitable for delivery to the bronchiole orbronchi regions. Particles with an aerodynamic size range greater than 6micrometer, and more preferably 10 micrometer, are typically suitablefor delivery to the laryngeal region, throat or nasal passages.

In most cases, it is desired to achieve a high inhalable fraction and ahigh delivery efficiency, i.e., the fraction of the initial dose of drugthat reaches the desired region, in particular, in the lung. Thisdepends on various factors, in particular, on the characteristics of thegenerated spray plume, such as the propagation velocity of the plume,particle size and its distribution, fraction of small particles,fraction of gas or the like.

U.S. Pat. No. 4,627,432 discloses a device for administering medicamentsto patients, namely an inhaler. The inhaler comprises a disk-likeblister pack having a plurality of blister pockets arranged in a circle.Each blister pocket contains a dose of the powder. A plunger can open ablister pocket. When a blister is opened, the medicament can bewithdrawn by a patient inhaling through a mouthpiece.

International Patent Application Publication WO 2005/002654 A2 disclosesa passive device for dispensing individual doses of powder. The dosesare contained in respective pockets of a disc-shaped carrier and openedby outwardly rupturing a covering foil in axial direction by means ofpressure on an opposite side surface. The pockets are moveable in axialdirection into an airstream generated by breathing of a patient fordispensing a dose of powder from the pocket. The device providesindividual respective deaggregation flow paths for each pocket, splitairstreams allowing improved entrainment of powder, a cam mechanism foroutwardly rupturing the pockets, an indexing mechanism linked to the cammechanism, and a dose counter.

It is difficult to empty the respective pocket completely during adispensing operation. Incomplete emptying results in decreased deliveryefficiency. Some powder may be lost in the inhaler and not dispensedbecause the known solutions require relatively long paths for the powderuntil the powder reaches a nozzle and is actually dispensed. This mightreduce the delivery efficiency further. In addition, de-agglomeration ofthe powder is difficult.

International Patent Application Publication WO 2006/037636 A2 and thecorresponding U.S. Patent Application Publication 2007/272763 disclosean active dispensing device with an air pump for dispensing powderindividually from storage chambers in a common carrier. Preferably, anindividual deaggregation and outlet duct having a flat cross-section isassociated to each storage chamber.

International Patent Application Publication WO 2007/062721 A1 and thecorresponding U.S. Patent Application Publication 2007/163574 disclosean active dispensing device for dispensing a formulation as a spray. Thedispensing device comprises a storage device with multiple pre-metereddoses of the formulation in separate inserts. The dispensing devicecomprises a means for pressurizing gas, in particular, an air pump, forgenerating a gas stream flowing through the respective insert fordispensing a dose of the formulation.

In general, it is very difficult to empty storage chambers or the likewhen the formulation is dispensed by means of a gas stream. Further,de-agglomeration of the formulation is difficult. Therefore, there is aneed to allow an optimized dispensing effect (better emptying of storagechambers or the like and/or better de-agglomeration) when theformulation is dispensed by means of a gas stream.

SUMMARY OF THE INVENTION

In accordance with the present invention, the desired spray plumecharacteristics preferably include a small particle size, a highfraction of drug particles with a diameter of 6 μm or less, a lowpropagation velocity and/or a long duration of spray generation andpossible inhalation.

The present invention relates to the dispensing of a preferably medicalformulation. The term “formulation” relates in particular to powder, butmay include or relate to liquids as well. Consequently, the fine“particles” may be either solid or liquid. The term “liquid” has to beunderstood preferably in a broad sense covering inter alia solutions,suspensions, suslutions, mixtures thereof or the like. Moreparticularly, the present invention relates to the dispensing offormulations for inhalation, such as medical formulations containing orconsisting of at least one drug.

In the following, the description will focus mainly on powderformulations. However, the same applies for liquid formulations.

In particular, the present invention is concerned with dry powderinhalers for the delivery of drugs to the lungs. Many dry powderinhalers are on the market or have been proposed. There are two maintypes, namely the passive ones and the active ones. In passive inhalersall the energy required for de-agglomerating the powder and transferringthe powder to the lungs is provided by the breathing of a user,respectively the patient. In active inhalers there is an additionalsource of energy to help to transfer and de-agglomerate the powder.

Most powder inhalers are of the passive type where the powder is inhaledby the patient without the aid of an additional energy source. Theproblem with passive inhalers is that the inhalable fraction, or theproportion of powder that actually enters the lungs, is largelydependent on the breathing of the patient. The transfer andde-agglomeration of the powder and hence the inhalable fraction is afunction of the flow rate of inhaled air through the device and,therefore, varies greatly from patient to patient.

Dry powder inhalers are subdivided into single dose and multi-dosedevices or inhalers. Multi-dose inhalers are further subdivided intopre-metered types where the doses are stored individually and intometering inhalers where each powder dose is metered in the device.

Multi dose pre-metered inhalers have the advantage that the single dosesare metered under strict factory conditions and the powder can quiteeasily be isolated from the atmosphere. In many applications the activedrug powder is mixed with a carrier such as lactose. The lactose and/oractive drug(s) tend to absorb humidity from the atmosphere, which makesthem stick together and difficult to transfer and de-agglomerate.

The present invention relates, in particular, to an active, gas(preferably air) powered, pre-metered multi-dose dispensing device fordispensing a formulation containing or consisting of a drug, such as adry powder inhaler.

A primary object of the present invention is to provide an improveddispensing device, storage device and method for dispensing a preferablymedical formulation, in particular wherein an optimized dispensingeffect can be achieved to dispense a preferably powdered formulation bymeans of a gas stream.

The above object is achieved by a dispensing, by a storage device and bya method as described herein.

According to a first aspect of the present invention, pressure pulsesare generated in the gas stream during dispensing of one dose.Alternatively or additionally, the direction of gas flow alternatesduring dispensing one dose of the formulation. Thus, a significantlyimproved dispensing effect can be achieved. In particular, theformulation may be entrained or loosened by the gas stream moreeffectively. Further, the formulation can be deagglomerated moreeffectively.

According to a second aspect of the present invention, the duct fordispensing the formulation, and in particular, generating the spray, isconnected to its associated storage chamber containing the dose of theformulation to be dispensed via a sharp edge or sharp transitionportion. Thus, a better dispensing effect can be achieved. Inparticular, a tapered transition portion is avoided between the largestorage chamber and the small duct. This avoids clogging of thetransition portion and, therefore, improves the dispensing effect of thegas stream.

Preferably, the gas stream is generated or enabled by a gas pressurizingmeans, i.e., preferably, the dispensing device is an active inhaler orthe like.

According to an alternative embodiment, however, the gas stream may alsobe generated by breathing in by a user or patient. Then, the dispensingdevice is, in particular, a passive inhaler.

Preferably, receptacles or cavities of the storage device respectivelycomprise a moveable insert as storage member with the respective dose offormulation. Preferably, each insert comprises a duct in order todirectly form the spray during use. Thus, the spray is generated by therespective insert when pressurized gas is supplied. This makes itpossible to respectively generate sprays with the desired spray plumecharacteristics with high accuracy.

Further aspects, advantages and features of the present invention willbe apparent from the following detailed description of preferredembodiments in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic sectional view of a dispensing device with astorage device according to an embodiment during dispensing;

FIG. 2 is a schematic sectional view of the storage device with aninsert;

FIG. 3 is a schematic sectional view of the insert;

FIG. 4 is another schematic sectional view of the storage device withpierced insert;

FIG. 5 a is a schematic view of the dispensing device;

FIG. 5 b is a graph of the pressure over time;

FIG. 5 c is a graph of the stroke of a pump part over time;

FIG. 6 is a schematic view of another dispensing device;

FIG. 7 is a schematic view of a dispensing device according to anotherembodiment;

FIG. 8 is a schematic view of inner components of the dispensing deviceaccording to FIG. 7 with the air assembly retracted;

FIG. 9 is a schematic view of inner components of the dispensing deviceaccording to FIG. 7 with the air assembly advanced in an activatedstate; and

FIG. 10 is a schematic view of inner components of the dispensing deviceaccording to FIG. 7 with the air assembly advanced after dispensing.

DETAILED DESCRIPTION OF THE INVENTION

In the figures, the same reference signs are used for the same orsimilar parts and components, wherein, preferably, the same or similarfeatures, aspects and/or advantages are achieved in the differentembodiments, even if a repetition of the respective description isomitted.

FIG. 1 shows in a schematic sectional view—for illustration purposes andnot to scale—a dispensing device 1 according to the present invention.The dispensing device 1 is preferably an active device, in particular,gas powered. Preferably, the dispensing device 1 is a preferably oral ornasal inhaler, in particular, a dry powder inhaler, for a user,respectively a patient (not shown).

Preferably, the dispensing device 1 is portable and/or hand-held.

The dispensing device 1 may be used for dispensing any formulation 2 asdefined in the introductory part of the description. In particular, amedical formulation 2 for inhalation will be used. The formulation 2preferably contains or consists of at least one drug. When theformulation 2 is dispensed, a spray 3 is generated as indicated inFIG. 1. The spray 3 includes or consists of fine particles (solid and/orliquid), and preferably, has the desired spray plume characteristics.

The formulation 2 may be a liquid, in particular, a solution, asuspension or any mixture thereof, i.e., a so-called suslution.Preferably, when different drugs are dispensed simultaneously, asuslution may be used. The principle of the suslution is based on thatdifferent drugs may be combined in one formulation simultaneously as asolution and as a suspension. In this respect, reference is made toEuropean Patent Application Publication EP 1087 750 A1 and correspondingU.S. Pat. No. 6,423,298, which are hereby incorporated herein byreference in this respect.

Preferably, the formulation 2 is a powder. The powder may be a pure drugor a mixture of at least two drugs or any other mixture of at least onedrug. In addition, the powder may contain at least one other material,in particular, a drug carrier, such as lactose. In the following, thedescription focuses on powder as formulation 2. However, this applies ina similar manner if a liquid formulation 2 is used.

Preferably, the mean diameter of the powder particles is about 2 to 7μm, in particular, 6 μm or less. This applies in particular if thepowder does not contain any drug carrier, such as lactose.

If the powder contains a drug carrier, such as lactose, and at least onedrug, the powder 2 may have a particle size of 20 to 300 μm, inparticular, about 30 to 60 nm. However, the de-agglomeration, which willbe described later in more detail, may result even in this case in aspray 3 with a smaller particle size, e.g., of about 10 μm or less. Inparticular, the drug may be separated from the drug carrier duringde-agglomeration so that primarily the drug will be inhaled due to itssmall particle size of about 2 to 6 μm and the larger drug carrier willbe swallowed when using the dispensing device as an inhaler.Alternatively or additionally, breaking or opening of the drug carrieris possible during de-agglomeration.

The diameters mentioned above and below may be understood as mass mediumaerodynamic diameters and/or may apply to the particle size or afraction of the particles of the spray 3.

Preferably, the formulation 2 is pre-metered in separate or individualdoses, which can be discharged one after the other by the dispensingdevice 1, in particular, for inhalation.

The dispensing device 1 is adapted to receive or comprises a storagedevice 4 for storing preferably multiple and pre-metered doses of theformulation 2. The storage device 4 may be integrated into thedispensing device 1 or form part of the dispensing device 1.Alternatively, the storage device 4 may be a separate part that can beinserted or connected with the dispensing device 1 and optionallyreplaced.

FIG. 2 shows a schematic cross-section of the preferably ring-likestorage device 4.

The storage device 4 preferably comprises a carrier 5 and at least onestorage member, preferably multiple storage members. Preferably, thestorage members are inserts 6. Therefore, the word “insert” is used inthe following.

In particular, the carrier 5 may comprise or support 20 to 100,preferably 30 to 60 inserts 6. Each insert 6 contains preferably onepre-metered dose of the formulation 2. However, each insert 6 may alsocontain more than one formulation 2, i.e., different formulations 2.Additionally or alternatively, different inserts 6 may contain differentformulations. In the present invention, “different” means in particularthat the formulations 2 differ in at least one of the composition, thedrug, the dose or amount, the concentration, and consistence of theformulation 2, e.g., liquid or dry powder.

The storage device 4 or carrier 5 preferably comprises multiple cavities7 or receptacles for receiving or with the inserts 6. In particular,each insert 6 is located in a separate cavity 7. Preferably, thecavities 7 are separate from each other, and in particular, sealedrelative to each other.

In the present embodiment, each cavity 7 comprises at least one opening8, in particular, two preferably opposed openings 8 (here, at theradially inner and outer circumference or periphery).

The cavities 7 or its openings 8 are covered by respective covers orseals 9 which are preferably formed by, preferably, heat-sealed foils onopposite sides of the respective cavity 7 or the carrier 5. In thepresent embodiment, the seal 9 is, in particular, a metallic foil, suchas aluminum foil, plastic foil, a multi-layer arrangement or the like.The seal 9 preferably protects the inserts 6 and/or formulation 2against humidity, dirt, moisture and/or the like. The seals 9 arerespectively resistant and/or impermeable, in particular, gas-tight.

In this preferred embodiment, the storage device 4 or carrier 5 isring-like and the cavities 7 extend at least substantially in radialdirection. The cavities 7 are distributed around the perimeter of oralong the storage device 4 or carrier 5, preferably equally spaced withrespect to the adjacent cavities 7.

In the present embodiment, the storage device 4/carrier 5 is preferablyrotatable around axis 13 shown in FIG. 1. In particular, the dispensingdevice 1 can be opened and the storage device 4/carrier 5 can beinserted or replaced.

The carrier 5 may be a molded element, a ring, a stripe, a cartridge, ablister or a container. Preferably, the storage device 4 or carrier 5 isrigid or at least essentially stiff.

Preferably, the carrier 5 is made of foil, plastics, ceramics and/orcomposite material, in particular, of thermoplastics or thermoplasticelastomers.

Each cavity 7 or receptacle preferably forms a guide for the associatedinsert 6, in particular so that the insert 6 is moveable in at least oronly one direction and/or at least or only partially out of the cavity 7or receptacle.

FIG. 1 shows a situation, where the insert 6 on the right side hasalready been pushed partially out of its associated cavity 7 and/or theouter opening 8 and/or through the respective seal 9 of its associatedcavity 7 for opening the seal 9. The insert 6 shown on the left side ofFIG. 1 is still within its closed and sealed cavity 7.

Each insert 6 is preferably produced filled with the respective dose offormulation 2 separately from the storage device 4 or carrier 5 and,then, inserted into its respective cavity 7 or receptacle.

Preferably, each insert 6 is molded and/or made of foil, plastics,ceramics and/or composite material, in particular of thermoplastics orthermoplastic elastomers and for seals of elastomers or silicone.

According to a preferred embodiment, the carrier 5 and/or the inserts 6are made of at least one of the following materials or any mixture orblend thereof:

ABS (acrylonitril-butadiene-styrene copolymer); SAN(styrene-acrylonitril-copolymer); PBT (polybutylene terephthalate); PC(polycarbonate); CA (cellulosic acetate); EVA (ethylene vinylacetatecopolymer); PA (polyamide); PE (polyethylene); PP (polypropylene); PMMA(polymethylmethacrylate); POM (polyoxymethylene, polyacetal); PPS(polyphenylene sulfide); PS (polystyrene); PBTP (polybutyleneterephthalate); TPU (thermoplastic polyurethane); blend of PC and PBTP;blend of PC and ABS; LCP (liquid crystal polymers); PHCS (polypyrrolorpolythiophene); PPA (polyphthalamide); PSU (polysulfone); PTFE(polytetrafluorethylene); PUR (polyurethane); SB (styrene-butadienecopolymer); PIB (polyisobutylene); PAN (peroxyacyInitrate); PET(polyethylene terephthalate); AMMA (acrylonitril-methymethacrylatcopolymer); PAR (polyarylate); PEEK (polyetheretherketone); COC(cycloolefine copolymer).

Each insert 6 may form a preferably block-like unit and/or be rigid.Alternatively, the inserts 6 may be flexible. In particular, each insert6 may be a unitary unit or made of multiple elements. In particular, theinsert 6 forms one component or is made of one piece. Each insert 6 maybe a molded element, a cartridge, a blister, a capsule, a container orthe like.

In the following, a preferred construction of one insert 6 is explained.Preferably, all inserts 6 are identical. However, it is also possiblethat all or some inserts 6 are different. For example, two or moregroups of different inserts 6 can be provided. It is possible that onegroup has a different dose or different formulation 2 than the othergroup. For example, the inserts 6 of the different groups could bearranged alternately one after the other so that a patient or user mayuse, for example, each morning an insert 6 of one group and each eveningan insert 6 of the other group.

Each insert 6 preferably comprises a storage chamber 10 for a singledose of the formulation 2. The schematic sectional views according toFIGS. 2 & 3 show a preferred embodiment of the insert 6. The schematicsectional view according to FIG. 4 is taken along line IV-IV of FIG. 3and shows the insert 6 when the insert 6 has been pushed out from thecarrier 5 and opened/pierced.

The insert 6 comprises a storage chamber 10 for the formulation 2. Inthe present embodiment, the storage chamber 10 is preferably formed in amolded base member 11 of the insert 6.

The insert 6/base member 11 further comprises a duct 12 or the like fordeagglomerating and/or discharging the formulation 2 during thedispensing operation. The formulation 2 is dispensed through the duct 12during the dispensing operation, in particular for directly forming thespray 3.

Preferably, the duct 12 is flat and/or rectangular in cross section. Inparticular, the cross section corresponds to a hydraulic diameter ofless than 1 mm. In particular, the duct 12 is designed as described inInternational Patent Application Publication WO 2006/037636 A2 andcorresponding U.S. Patent Application Publication 2007/272763, which arehereby incorporated by reference.

According to another embodiment (not shown), the duct 12 can also beused as a reservoir (storage chamber 10) for the formulation 2. In thiscase, the separate storage chamber 10 is not required. Then, the duct 12is designed to enable sufficient mixing of the gas with the formulation2 and sufficient de-agglomeration of the powder formulation 2.

Preferably, the spray 3 having its desired spray characteristics isdirectly ejected or discharged from the insert 6/duct 12 or is generatedby the duct 12 only.

In particular, the insert 6 forms one component or is made of one piece.

The insert 6 or duct 12 can comprise or form a nozzle arrangement,preferably, at an outlet 15 or end of duct 12 or formed by duct 12.

Preferably, the storage chamber 10 and/or the duct 12 is formed by or inthe base member 11, in particular, by a recess, groove or the like inthe base member 11 and by an associated cover member 14 as shown in FIG.4. In particular, the duct 12 forms a channel from the storage chamber10 to the outlet 15 of the insert 6, in particular, for directlydischarging or dispensing the formulation 2 as spray 3 as shown inFIG. 1. Preferably, the base member 11 is molded and/or rigid.Preferably, the cover member 14 is rigid and/or rigidly fastened, e.g.,welded, to the base member 11.

It is noted that the inserts 6 may be or are preferably open, i.e., notsealed, in particular, at their respective outlet 15 only. Experimentshave shown that sealing of the carrier 5/cavity 7 is sufficient. Theduct 12 is preferably so small in cross section or provided with abursting element or any other suitable means that the formulation 2 isnot discharged, preferably, even with seal 9 opened and/or during strongshaking of the dispensing device 1/storage device 4, but preferably,only when gas (air) is forced through the insert 6 and duct 12.

The inserts 6 and cavities 7 are preferably adapted to each other suchthat the seals 9 contact end faces of the inserts 6, and thus, cover theoutlets 15. This may further prevent any formulation 2 from dissipatingthrough the duct 12/outlet 15 before the desired dispensing. In order toincrease the seal or cover effect produced by seal 9, the inserts 6 maybe slightly longer than the cavities 7 and/or protrude at their outletside and/or be pressed with their outlets 15 against the seals 9 or viceversa.

The insert 6 preferably comprises an inlet for supplying preferablypressurized gas into the storage chamber 10 to force the formulation 2through the duct 12 and to directly generate the described spray 3. Inthe present embodiment, the inlet is preferably formed by a weak orthinned portion and/or designed as a preferably tube-like recess 16 orblind bore formed in the base member 11. Preferably, the recess 16 isnot directly connected to the storage chamber 10, but is separated by aseal or an intermediate or thinned wall or the like. This wall can bepenetrated, e.g., by a connecting element, preferably a piercing element17, such as a needle, as shown schematically in FIG. 6, or by any othersuitable opening, connecting and/or supply means, in particular, whenthe respective insert 6 is connected to a gas supply as explained in thefollowing. Preferably, the piercing element 17 is a hollow needle, inparticular, with a solid or closed tip 17 a and a side opening 17 badjacent the tip 17 a for supplying the pressurized air into the insert6/storage chamber 10.

In the present invention, the expression “piercing element 17”preferably covers also all other suitable types of means for openingand/or connecting the storage device 4, the carrier 5, a cavity 7 and/oran insert 6 and/or for directly or indirectly supplying gas to an insert6 or its respective storage chamber 10.

It is noted that the cross sections of the inserts 6 and the cavities 7are preferably polygonal, in particular, rectangular or that otherguiding means are preferably provided, in order to avoid that theinserts 6 may pivot within the cavities 7. However, if the inserts 6 arerotatably symmetrical with respect to the recess 16 or any otherconnection/inlet for gas supply and with respect to its outlet 15, theinserts 6 may also be cylindrical and/or can rotate within the cavities7. This may facilitate insertion of the inserts 6 into the cavities 7during production.

The duct 12 is preferably at least tangentially connected to the storagechamber 10 as shown in FIG. 3. Preferably, the duct 12 is connected atone axial end of the preferably cylindrical chamber 10, and the gasinlet (recess 16/piercing element 17) is connected or connectable to theother axial end of the chamber 10 as indicated in FIG. 4. In particular,the gas inlet is connected also tangentially to the storage chamber 10,such that swirls are generated when entering the gas with a swirldirection supporting discharge of the mixture of gas and formulation 2through the duct 12, which connects tangentially to the rotationaldirection of the swirl.

Preferably, the duct 12 is connected to its associated storage chamber10 via a sharp edge or transition portion 45 as shown in FIG. 4. Inparticular, the ducts 12 have an at least essentially constant crosssection which preferably begins at an entry port or opening 46 of theduct 12 at an inner side wall 47 of the storage chamber 10.

In particular, the storage device 4 or storage member/insert 6 does notcomprise a tapered transition portion 45 where the storage chamber 10and the duct 12 are interconnected. Thus, clogging of the formulation2—in particular, in this transition portion 45—can be avoided or atleast minimized.

The transition portion 45 preferably has a constant cross section, formsthe beginning of the duct 12, forms the entry opening 46 of the duct 12,and/or is not tapered.

Therefore, an improved dispensing effect can be achieved.

The dispensing device 1 uses preferably pressurized gas, in particular,air, to force the formulation 2 through the duct 12 to de-agglomeratethe powder and/or to generate the spray 3 with fine powder particles.Preferably, the dispensing device 1 comprises a means for providingpressurized gas, in the present embodiment an air pump 18, as indicatedin FIG. 1, which can preferably be actuated or operated manually, e.g.,as indicated by handle or actuator 19 and/or by a spring means as shownlater in another embodiment.

In particular, the air pump 18 comprises or is formed by a bellows 27 asschematically shown, e.g., in FIG. 5 a. but, it could be also apiston-cylinder-arrangement. Instead of the air pump 18, the means forproviding pressurized gas can be, e.g., a capsule, container or the likecontaining pressurized or liquefied gas for powering the dispensingdevice 1, i.e., dispensing the formulation 2 as desired. Therefore, theterm “means for pressurizing gas” has to understood preferably in abroad sense to cover these and similar alternatives to the pump 18 aswell.

The means for providing pressurized gas/air pump 18 may provide a gaspressure of less than 300 kPa, in particular, about 50 to 200 kPa. Thisis preferably sufficient for operating the dispensing device 1. Ifliquefied gas or a container with pressurized gas is used, the gaspressures might range from 100 kPa to about 700 kPa. Then, the pressuremay be reduced or throttled to the preferred pressure range beforesupplying the gas to the storage device 4, in particular, the storagechamber 10 of the respective insert 6.

Preferably, all pressure values mentioned in the present description aregauge pressures, i.e., pressure differences. All pressure values relateto the pressure in a gas storage, such as a container with pressurizedor liquefied gas, or provided by air pump 18 or relate to the pressuresacting in the chamber 10 and/or in the duct 12.

FIGS. 1 & 5 a show that the dispensing device 1 preferably comprises amechanism 20 for individually opening the cavities 7, for individuallymoving the inserts 6, preferably radially (here outwardly) and/orthrough an associated opening 8 and/or seal 9, and/or for individuallyconnecting the inserts 6 to the gas supply, in particular, to the airpump 18. The mechanism 20 preferably comprises the piercing element 17and/or any other suitable connecting or actuation element.

In particular, in a first operation phase the piercing element 17penetrates the seal 9 and, then, is inserted into the recess 16 andthrough the intermediate, end or weakened wall into the storage chamber10 and, thus, connects the respective insert 6 to the gas supply.Before, simultaneously or afterwards, e.g., during the further movement,the mechanism 20 pushes the insert 6 through the other or outer opening8 and through the respective seal 9 at least partially out of its cavity7. Preferably, the mechanism 20 acts directly on the respective insert 6to cause its movement. Here, the piercing element 17 is preferablyprovided with a shoulder or abutment or sleeve 21 (shown schematicallyin FIG. 6) that abuts against the insert 6 to positively produce thedesired movement of the insert 6 when moving the mechanism 20/piercingelement 17. The final situation is shown in FIG. 1 on the right side andin FIG. 6 with protruding insert 6.

It is noted that any other driving mechanism can be used to move theinsert 6 to open one opening 8/one seal 9/the respective outlet 15 orthe insert 6, itself. In particular, it is possible to realize thepreferred pushing of the insert 6 through the seal 9 independently ofthe connecting or piercing of the insert 6.

In order to facilitate opening of the respective seal 9, the insert 6comprises preferably an opening means, in particular, a tip portion 11b, and/or is tapered at its outlet end. In particular, the insert 6 orits base 11 comprises an inclined portion 11 c—preferably, at least oronly on one flat side of the insert 6 or base 11—so that the insert6/base 11 is tapered towards the outlet 15, as shown schematically inFIGS. 4 & 6. Thus, it is possible to form a tip or tip portion 11 b,which forms a front face with reduced or minimal surface. It is evenpossible to form a cutting edge at the outlet end.

Alternatively or additionally, it is possible to form or provide anyother suitable cutting element as opening means at the insert 6, inparticular, at its outlet end.

In particular, the stroke or outward movement of the insert 6 is adaptedand preferably so long, such that the desired opening of the seal 6 isensured, and in particular, that the broken, cut and/or rupture parts ofthe opened seal 9 cannot hinder or cover or interfere with the outlet 15of the insert 6. In the present embodiment, the seal 9 substantiallyruptures at one side of the opening 8 where the tip portion 11 b of theinsert 6 is located. The short rest of the seal 9 mounted on this sideof the opening 8 cannot interfere with the outlet 15 of the protrudinginsert 6 because it is preferably shorter than the outward stroke of theinsert 6. The longer part of the seal 9 connected to the other side ofthe opening 8 will be bent or pivoted away by the insert 6.

In the present embodiment, the opening and/or cutting of the seal 9takes place at one side or adjacent to one edge of the preferablyrectangular opening 8 when the respective insert 6 is moved outward ofits cavity 7 for activating and later dispensing. The opening means, tipportion 11 b, cutting element or the like is located at one side of theinsert 6, and in particular, adjacent to one side of its cavity 7 andopening 8 so that the mentioned opening of the respective seal 9 occursas described when the insert 6 is moved outward. With other words, thelocation of the opening or cutting means may be and, in particular, isused to ensure or cause a desired opening pattern and/or location of therespective seal, in particular at one side and/or adjacent to one edgeof the opening 8. However, other opening locations can be chosen. Forexample, it is also possible to open the respective seal 9 in thecenter. Additionally or alternatively, the insert 6 may be adapted—inparticular, by provision of two or more opening or cutting means—to openor rupture or cut the respective seal 9 at multiple regions subsequentlyor simultaneously.

In the present embodiment, the insert 6 is preferably moveable radiallyand/or outwardly and/or away from the airpump 18 and/or in itslongitudinal direction and/or in the main discharge direction and/or inthe main extension of the mouthpiece 24. However, other movements arealso possible. In the present case, only a translational movement isprovided. However, a rotational or pivotal movement can be providedadditionally or alternatively or superposed.

Preferably, the storage device 4, the carrier 5 and/or the cavities 7comprise means for limiting the possible or maximum movement of theinserts 6. Preferably, this means stops the insert(s) 6 by form-fit. Inthe present embodiment, the means comprise stops 22, e.g., shoulders,protrusions or the like, which interact with a respective abutment, suchas a shoulder 23, of the respective insert 6 so that the insert 6 islimited in its movement out of the respective cavity 7, as shownschematically in FIG. 4, where the shoulder 23 abuts the respective stop22, and thus, prohibits any further outward movement of the insert 6.However, it is noted that any other technical solution having the sameeffect can also be used.

For dispensing, the gas (air) is supplied under pressure to the storagechamber 10 via the piercing element 17 or any other suitable connectingor supply element.

The gas (air) generates a respective flow in the storage chamber 10 tomix gas and powder and to force the dose through the duct 12.

FIG. 5 a shows a preferred construction or design of the dispensingdevice 1. In this embodiment, the means for pressurizing gas (air pump18) comprises the bellows 27 for pressurizing gas, in particular, air.The bellows 27 may be actuated by a spring means, in particular, aspring 28, as schematically shown. In particular, the spring meanscompresses the bellows 27 during the dispensing operation to pressurizethe gas and to supply the gas to the connected storage device 4/storagemember/insert 6/storage chamber 10 via the connecting or supplymechanism 20/connecting element/piercing element 17. Thus, a gas streamis generated, as shown by arrows 40, during the dispensing operation.The gas stream 40 flows through the storage device 4/storage chamber 10,entrains the respective dose of the formulation 2 and is ejected via theduct 12 to generate the spray 3, as schematically shown in FIG. 5 a.However, other constructions, in particular, of the means forpressurizing gas, are possible.

Preferably, the dispensing device 1 or storage device 4 or means forpressurizing gas comprises a throttle for throttling the gas stream 40.In the present embodiment, the throttle is formed by a restrictionand/or the connecting element, i.e., here by the hollow needle orpiercing element 17. However, other constructional solutions arepossible.

Preferably, the throttle is located stream up, in particular, justbefore, the storage chamber 10. However, it is also possible to form thethrottle within the storage chamber 10 or downstream thereof, inparticular in or by the duct 12 or the like. In one embodiment (notshown), the throttle may be formed at or by the transition portion 45 orthe entry opening 46 of the duct 12.

According to one aspect of the present invention, the dispensing device1 is designed such that pressure pulses 41 are generated in the gasstream 40 during dispensing one dose of the formulation 2 as shown in anexemplary manner in the schematic pressure diagram or curve according toFIG. 5 b.

FIG. 5 b is a very schematic diagram. The curve shows the pressure pover the time t. The pressure curve p shows in an exemplary manner thatpressure pulses 41 occur during the dispensing operation or period, herefrom time t₀ to t₁.

The pressure p approaches during the period of dispensing a maximumpressure p_(m) as schematically shown in FIG. 5 b. However, thisbehavior may vary very strongly depending on the dispensing device 1,storage device 4 and the like.

According to the preferred embodiment, the pressure pulses 41 aregenerated by a respective resonance system, preferably formed betweenand/or by the throttle and/or air pressurizing means.

Alternatively or additionally, the pressure pulses 41 can be generatedby means of a valve or the like in the gas supply, e.g., by means ofvalve 44 mentioned later.

Preferably, the bellows 27 and/or spring means, such as the spring 28,oscillate or vibrate during the dispensing operation caused by thepressure pulses 41 or causing the pressure pulses 41.

The schematic diagram of FIG. 5 c shows the stroke or amplitude orcompression of the bellows 27, of a pump piston or of the spring 28 overthe time t. It can be seen from the curve that the stroke relativelyquickly increases to its maximum stroke s_(m), and then, oscillatesduring the period of dispensing from t₀ to t₁ resulting in the pressurepulses 41.

Preferably, 2 to 5 pressure pulses 41 are generated during eachdispensing operation.

The pressure pulses 41 preferably comprise a decrease of the gaspressure by at least 300 kPa/s, in particular at least 500 kPa/s ormore. These pressure drops or decreases occur during the dispensingoperation, i.e., when the gas stream 40 flows through the storage device4. In particular, this pressure decrease does not relate to the pressuredrop at the end of the dispensing process.

The pressure pulses 41, and in particular, the associated variations ofthe flow rate of the gas stream 40 can loosen the formulation 2.

Further, the pressure pulses 41 can generate or result in higher shearforces so that de-agglomeration of the formulation 2 is enhanced.

Additionally or alternatively, the pressure pulses 41 may prohibit anyclogging of small openings, chambers, channels or the like, inparticular of the duct 12.

According to a further aspect of the present invention, which aspect canbe realized alternatively or additionally, the direction of gas flow,i.e., of the gas stream 40, alternates, preferably at least once, inparticular, at least 2 to 5 times, during a dispensing operation orprocess. This change of the flow direction results in the same orsimilar advantages as described above with respect to the pressurepulses 41. In particular, the alternation of the flow direction can becaused by the pressure pulses 41 and/or by a respective oscillation of apiston, of the bellows 27 or the like of the means for pressurizing gas.However, other constructional solutions are possible as well.

Preferably, the flow direction of the gas stream 40 is reversed only fora very short period with respect to the total period of the dispensingoperation or process. In particular, the short period of reversing theflow direction is at most 5%, in particular about 2% or less, of thetotal period of the inhalation operation or process.

The powder will be discharged—in particular, forced through the duct12—with a comparatively low gas pressure (preferably less than 300 kPa,in particular, about 50 kPa to 200 kPa). This low gas pressure, which issignificantly lower than the gas pressures in the prior dispensingdevices, enables a respectively low discharge velocity, and therefore, aslow spray 3 with slow propagation velocity.

Preferably, the storage chamber 10 forms a mixing chamber for mixing thegas with the powder. The chamber 10 is preferably designed such that thegas can generate swirls or eddies for better mixing the powder with thegas. Preferably, the chamber 10 is substantially circular in crosssection, in particular cylindrical. However, other shapes are alsopossible.

Further, the chamber 10 is formed with no sharp edges, corners or thelike, but has a smooth contour so that the gas can sweep all chambersurfaces to prevent powder accumulating on them and to ensure or allowcomplete discharge of the powder. In particular, the gas inlet formed bythe piercing element 17 or any other supply element is located oppositeto the outlet, i.e., duct 12 and/or nozzle 13, with regard to the axialor outlet direction.

During the dispensing operation, the spray 3 is preferably directly oronly generated by the respective insert 6 or its duct 12 and output intoa mouthpiece 24 of the dispensing device 1 as shown in FIGS. 1 & 5 forinhalation by a patient or user.

After dispensing one dose, or before or for dispensing the next dose,the piercing element 17 will be withdrawn from the connected insert 6.Preferably, the respective insert 6 is also retracted or pushed backinto its cavity 7.

Then, the carrier 5 will be indexed one step further or to the nextinsert 6, in particular, rotated by means of an indexing or transportmechanism (not shown). This mechanism is preferably operated byactuating actuator 19 or any other actuator, by opening a cap or coverof the dispensing device 1 or the like, as already mentioned.

It is noted that the present invention, in particular, the dispensingdevice 1 and/or the storage device 4, can be used for dispensing onedrug, a blend of drugs or at least two or three separate drugs. In thelatter case, the separate drugs are stored in separate storage chambers10, and during the dispensing operation, the drugs are mixed with thegas, either in a common mixing chamber or in their respective storagechambers 10. Further, the separate drugs can be discharged through acommon duct 12 or through separate ducts 12. In the latter case, theseparate drugs will be mixed after leaving the separate ducts 12 or inthe mouthpiece 24 or in any other suitable (additional) mixing chamber.It is also possible to mix the separate drugs by impinging jets of theseparate drugs. For dispensing the separate drugs, it is preferred touse a common gas supply or means for pressurizing gas such as air pump18.

Preferably, the spray 3 has a mean velocity (taken 20 cm from the outlet15 or mouthpiece 24) of less than 2 m/s, in particular, less than 1 m/s.Preferably, the mean duration of the spray 3 is at least 0.2 or 0.3 s,in particular, about 0.5 to 2 s.

In the preferred embodiment according to FIG. 1, the cavities 7 areorientated in tangential or radial direction of the storage device 4 orcarrier 5. Consequently, the inserts 6 can be individually moved intangential or radial directions, in particular, outwardly, in order toopen the respective outer seal 9 for dispensing the respective dose ofthe formulation 2 as indicated in FIG. 1. Accordingly, the mechanism 20preferably operates in a radial direction for connecting the inserts 6individually to a gas supply and for pushing the inserts 6 individuallyat least partially out of the respective cavity 7 and/or through therespective seal 9. This radial movement allows a very compact design ofthe dispensing device 1, in particular, in the axial direction.

Preferably, the mouthpiece 24 and the dispensing direction extend in aradial or tangential direction, as shown in FIG. 1.

Preferably, the dispensing device 1 comprises a lever or handle (notshown) or the actuator 19 or any other driving or actuation means forpreferably manual actuation in order to index the carrier 5 one stepfurther, i.e., to the next insert 6, and/or to operate the mechanism 20,preferably to connect the respective insert 6 to the gas supply and/orto move/push the respective insert 6 and/or to open the respective seal9 for dispensing the respective dose of the formulation 2.

It is noted that the dispensing device 1 operates preferably onlymechanically.

According to another embodiment (not shown), the inserts 6 may be formedas capsules, blister pockets or the like without any duct 12, or thelike. Instead, each insert 6 is connected individually to a gas supplyand to a common outlet arrangement, such as a duct 12, nozzle or thelike for dispensing the respective dose of the formulation 2.

According to another embodiment, a secondary packaging may be used forpacking and protecting the storage device 4/carrier 5, in particular forstorage purposes, before inserting the storage device 4/carrier 5 intothe dispensing device 1. Additionally, the whole device 1, including thestorage device 4/carrier 5, may be stored in a secondary water vaporproof packaging.

According to another embodiment shown schematically in FIG. 6, thedispensing device 1 may also be a passive inhaler wherein a patient oruser (not shown) forces sucks an air flow through the respectivelyopened insert 6, when breathing in so that this airflow entrains theformulation 2 and forms the desired spray 3 in the mouthpiece 24 forinhalation by the patient/user.

In particular, the dispensing device 1 comprises an air inlet 39 throughwhich the air can enter. The air inlet 39 is fluidically connected tothe connecting/supply means 20 and the connecting element/piercingelement 17 so that the air sucked in can form the gas stream 40 whichflows through the storage device 4/storage chamber 10 and dispenses theformulation 2 as spray 3 in the desired manner.

According to a further embodiment, the dispensing devise 1 may be breathactivated, in particular, wherein the formulation 2 is only releasedafter the patient's or user's inhalation rate has reached apredetermined level, preferably by the use of a pressure sensitivemeans, such as a bursting element, membrane or valve, or any othermechanism.

It is noted that the term “dispensing device” has to be understood in abroad sense to include other discharge devices, dispensers or the like,preferably wherein the formulation 2 or any other fluid is sprayed oratomized only when needed, in particularly discontinuously.

In the following, a further preferred embodiment of the dispensingdevice 1 will be explained with reference to the further drawings. Thefollowing description will focus on relevant differences between thefurther embodiment and the previous embodiments. In particular, theprevious explanations and descriptions apply accordingly and/oradditionally, even if not repeated.

FIG. 7 shows the further embodiment of the dispensing device 1 in aperspective view. The dispensing device 1 comprises a cover 25 forcovering the mouthpiece 24. Preferably, the cover 25 can be pivoted toopen or uncover the mouthpiece 24 as shown. Preferably, the mouthpiece24 is snapped to a housing 26 of the dispensing device 1.

The dispensing device 1 comprises the actuator 19 at one side of itshousing 26, preferably on the opposite side of the mouthpiece 24 and/oropposite to the main spray direction (preferably in a radial direction)of the dispensing device 1. The actuator 19 forms preferably a grip orhandle. Therefore, the term “grip” will be used in the following.

The grip 19 is preferably moveable in a radial direction for actuatingthe dispensing device 1 as explained later in more detail. Inparticular, the grip 19 can be pulled radially outwardly from theinitial position shown in FIG. 7 and pushed back into its initialposition. These operations may be named “pulling” and “pushing”,respectively, in the following. However, it is noted that theseoperational movements could also be realized by any other direction ortype of movement, such as a non-translational movement.

First of all, the basic principle of the dispensing device 1 will beexplained with reference to FIGS. 8 to 10. FIGS. 8 to 10 show only veryrudimentary schematic views (not to scale) of inner components of thedispensing device 1 for explaining the principle. In particular, thehousing 26 and the grip 19 have been omitted. Further, the storagedevice 4 is shown only in a schematic manner, in particular,incompletely or partially only in FIGS. 9 & 10. In particular, multipledetails, such as seals 9, outlets 15 or the like, have been omitted. Thepreferred construction of the storage device 4 will be explained laterafter explaining the basic functional principle of the presentdispensing device 1.

The dispensing device 1 is an active atomizer or inhaler. The means forpressurizing gas is preferably also constructed as air pump 18. Here,the air pump 18 comprises the bellows 27 as pumping element. However,any other suitable pumping element, such as a piston, could be used.

The dispensing device 1/air pump 18 further comprises an energy orspring store, in particular, the spring 28, for actuating the pumpingelement, i.e., the bellows 27.

The air pump 18 (bellows 27 and spring 28) is preferably radiallymoveable, in particular, in a sliding manner or like a sled. Preferably,the air pump 18 forms a slider 29 or is supported thereon. Inparticular, the air pump 18 and slider 29 will be called an “airassembly” in the following.

Preferably, the air assembly forms or includes the mechanism 20 alreadymentioned with respect to the previous embodiments. For this purpose,the air assembly preferably comprises a needle holder 30 holding thepiercing element/needle 17. The piercing element 17 may be pressedand/or glued or molded into the needle holder 30. Preferably, thebellows 27 is pressed or clamped onto the needle holder 30.

The needle holder 30 may be designed such that it can push therespective inserts 6 outwardly in case the sleeve 21 or any otherabutment fails.

The needle holder 4 preferably closes or completes the slider frame 31.For example, the needle holder 30 may comprise holds for pins of theslider frame 31, which pins may be heat-riveted.

The needle holder 30 is connected to or formed by a slider frame 31,which, in turn, holds the spring 28 and/or moveably guides a tensionelement 32 associated with the bellows 27 and/or spring 28.

In the embodiment shown, the bellows 27 is arranged between the needleholder 30 and the tension element 32. The spring 28 is arranged behindthe bellows 27, e.g., on the opposite side of the tension element 32.

The tension element 32 holds the bellows 27 in order to secure thefilling of the bellows 27 during pulling. Namely, the grip 19 preferablyretracts the tension element 32 during pulling.

The air pump 18 or air assembly is preferably located in the center ofthe dispensing device 1 and/or within the storage device 4 and/orring-like carrier 5 and/or is preferably radially moveable.

FIG. 8 shows the situation after the grip 19 (not shown) has been pulledout. The bellows 27 is extended and filled with air. The spring 28 iscompressed or tensioned, i.e., the energy store has stored energy. Thetension element 32 is retracted and locked in its position to hold thespring 28 in its compressed state. The air assembly/slider 29 isretracted so that the piercing element 27 is retracted from the storagedevice 4, in particular, so that the storage device 4 can be indexed ormoved, in particular rotated.

When the grip 19 is pushed back, preferably a transportation operationand a connecting operation will be performed.

In the first phase of the movement of the grip 19, a transport mechanism33 is actuated. In particular a cogwheel 34 of the transport mechanism33 (shown in FIG. 9) at least temporarily meshing with a preferablyinner teeth 35 of the storage device 4 or carrier 5 is rotated to moveor index the storage device 4 by one insert 6 or cavity 7 and/or to thenext insert 6 or cavity 7. However, it is noted that this transportationoperation could also be performed partly or completely during pulling.

Preferably after termination of the transportation operation, i.e.,during a second phase of pushing, the connecting operation is performed.The air assembly/slider 29 is moved forward and/or radially so that thepiercing element 17 connects to the next/aligned insert 6/cavity 7. Inparticular, the piercing element 17 pierces into the insert 6 to connectto its storage chamber 10. Before, simultaneously and/or subsequently,the insert 6 is moved radially and/or outward and/or pushed through theouter seal 9. Thus, the insert 6/duct 12/outlet 15 is opened. Thissituation is shown in FIG. 9, wherein the connected and opened insert 6is protruding radially outwardly from the storage device 4 and/or itscavity 7.

The spring 28 is still biased or compressed. This situation is alsonamed “activated state”. The dispensing device 1 is ready for dispensingthe dose of formulation 2 from the opened/protruding inserts 6 shown inFIG. 9.

To initiate delivery (discharge) of the formulation 2 and to generatethe spray 3, a release button 36 (shown in FIG. 7) or any other suitableelement is actuated, in particular depressed. Thus, the tension element32 or its associated locking means is unlocked (preferably bydepressing/compressing the elastic snap arm 32 a), and the spring 28 isreleased and compresses the bellows 27. The bellows 27 compresses theair contained therein. Thus, the air is pressed through piercing element17 into the connected insert 6. The resulting air stream is forcedthrough the connected insert 6, entrains the powder/formulation 2 of theinsert 6 and ejects as spray 3 (not shown).

FIG. 10 shows the final state after discharge. The spring 28 isexpanded. The bellows 27 is compressed. The tension element 32 has beenmoved forward to the needle holder 30/piercing element 17. The piercingelement 17 is still connected to the emptied insert 6, and the emptiedinsert 6 is still protruding outward. In this state, the dispensingdevice 1 can be closed and transported. Therefore, this state is alsonamed “transportation state”.

For the next use, the grip 19 is pulled. In a first phase of themovement, the slider 29/air assembly is retracted together with thepiercing element 17 so that the piercing element 17 is retracted fromthe storage device 4, i.e., out of the cavity 7 of the last insert 6. Ina second phase of movement, which can also happen simultaneously, but ispreferably performed after stop of the slider 29, the tension element 32is retracted within the slider 29/slider frame 31 so that the bellows 27is extended and the spring 28 is compressed or biased until the tensionelement 32 is locked in its retracted position as shown in FIG. 8.During the extension of the bellows 27, air is sucked into the bellows27, preferably through piercing element 17 and/or optionally through asuitable inlet valve (not shown).

It is noted that the release button 36 is preferably lifted only duringthe last phase of pushing the grip 19. Further, the lifted or activatedor primed release button 36 preferably blocks pulling of the grip 19until the release button 36 has been actuated or depressed, i.e., untilthe dispensing device 1 has been triggered. In particular, the releasebutton 36 is tilted during actuation or depressing.

In the following, further details, aspects, features and advantages ofthe present dispensing device 1 and/or of its components will beexplained.

Preferably, the storage device 4 comprises multiple receptacles 37respectively containing only or at least one insert 6, as schematicallyshown in FIG. 8 to 10. In particular, the receptacles 37 are produced asseparate parts that are placed or mounted on the carrier 5.

Preferably, the receptacles 37 are engaged in or held by recesses 38 onthe carrier 5.

The receptacles 37 may be made of the same material as the storagedevice 4/carrier 5, in particular of plastic. Preferably, thereceptacles 37 are rigid and form a guide for the inserts 6.

Each receptacles 37 comprises only one or multiple cavities 7 forreceiving the respective insert(s) 6.

Preferably, the receptacles 37 are provided with the inserts 6 alreadyfilled with the respective dose of formulation 2 and, then, mounted onthe comment carrier 5.

The receptacles 37 are preferably sealed separately, i.e., independentlyfrom each other and/or with separate seals 9. The receptacles 37 may besealed before or after placement on the carrier 5.

The receptacles 37 are preferably sealed on opposite sides and/or onlongitudinal end faces.

Preferably, the receptacle 37 has an essentially cuboid and/orlongitudinal form.

The carrier 5 preferably supports the receptacles 37 fixedly and/or in aform-fit manner. Preferably, the receptacles 37 are snapped on to orinto the carrier 5.

Preferably, the air assembly/slider 29 and the storage device 4/carrier5/receptacles 37 interact such that a correct alignment of the piercingelement 17 and the respective receptacle 37 or insert 6 is ensuredbefore the piercing element 17 pierces or opens the respectivereceptacle 37, cavity 7 and/or insert 6.

Preferably, the inserts 6 are restricted in their backward movement asalready mentioned so that the piercing element 17 can be retracted anduncoupled from the respective insert in a definitive manner when the airassembly/slider 29 is retracted into the position shown in FIG. 8.

In the present embodiment, a locking means is provided for locking thetension element 32 in the retracted position. Here, the locking meanscomprises at least one snap hook or arm 32 a, preferably two or moresnap arms 32 a engaging into respective undercuts, recesses or snapopenings 32 b preferably formed by or in a back shield 32 c of theslider 29 or slider frame 31 or vice versa. However, otherconstructional solutions are possible.

The dispensing device 1 is preferably an active powder inhaler, i.e.,the powder is discharged by pressurized gas, in particular air.Nevertheless, the dispensing operation may be triggered by theinhalation or breathing in of a patient (not shown). In particular, thedispensing device 1 may comprise detection means for detectinginhalation or breathing in and/or trigger means for triggeringdispensing of the respective dose.

Preferably, the detection means comprises a sensor 42 for detecting atleast one of a pressure, a pressure drop, a velocity, an increase ofvelocity or any associated value thereof regarding the air flowingthrough the dispensing device, in particular the mouthpiece 24, when apatient breathes in.

The respective detection signal indicating breathing in of a patient maybe used by the trigger means in order to trigger dispensing of therespective dose by means of pressurized gas. In particular, the triggermeans comprises a controller 43 and/or a valve 44 associated to themeans for pressurizing gas, in particular the air pump 18, a gas supplyline, the piercing element 17 or the like so that start of flow ofpressurized gas to and through the respective storage chamber 10 or thelike for dispensing the respective dose of formulation 2 may becontrolled or triggered.

Preferably, the trigger means operate electrically or electronically orpneumatically or mechanically. For example, the detection means andtrigger means may be formed only by an appropriate valve 44 that opensthe supply of pressurized gas through the respective receptacle 37,insert 6 and/or storage chamber 10 when the pressure in the mouthpiece24 drops due to breathing in of a patient. Then, the valve 44 preferablystays open until the flow of pressurized gas stops or the gas pressurereaches or drops bellow an appropriate pressure limit. Such afunctionality may be realized without using electric or electroniccomponents.

There are multiple other mechanism possible. According to anotherembodiment, a sealed outer case can have a flexible diaphragm, e.g.,made of rubber, mounted within its wall with one surface facing theinside and the other exposed to atmosphere. A linkage with mechanicaladvantage (amplification) connects the diaphragm to the tension element32 (FIGS. 8 and 9) or to the valve 44 or any other suitable means tocontrol gas supply. When the user or patient inhales via the mouthpiece24 the sealed case ensures a pressure reduction due to which bents thediaphragm into the case activating or acting on the mechanical link and,thus, triggers dispensing, in particular by releasing tension element32, opening valve 44 or the like.

According to another embodiment, a flap can be seally positioned withinthe mouthpiece 24 and connected to the tension element 32, the valve 44or the like via a linkage with mechanical advantage or amplification.When the user or patient inhales, the air flow/pressure difference opensor actuates the flap activating or operating the link and, thus,triggering dispensing, in particular by releasing tension element 32,opening valve 44 or the like.

According to another embodiment, an electronic system can be used. Apressure sensitive actuator can be connected to tension element 32 sothat tension element 32 can be released when detecting inhalation orbreathing in of a user or patient.

Preferably, the automatic triggering or dispensing is only possible whenthe dispensing device 1 has been activated and/or dispensing has beenallowed, in particular by actuating the release button 36 or any otheractuator, before the trigger means may eventually trigger the dispensingwhen breathing in is detected.

In case of the present preferred ring arrangement, the indexingdirection extends in the tangential and/or circumferential direction.The term “indexing direction” means preferably the direction in whichthe storage device 4 is moved, in particular rotated, stepwise from onereceptacle 37, cavity 7 or insert 6 to the next one so that therespective doses of formulation 2 can be discharged one after the other.

In particular, the dispensing device 1 is a preferably oral and/oractive inhaler, a hand-held device and/or preferably only manuallyoperated. Most preferably, the dispensing device 1 is a dry powderinhaler.

Individual features and aspects of the different embodiments may also becombined with one another as desired or used in other constructions ofatomizers, inhalers, dispensers or the like.

Some preferred ingredients and/or compositions of the preferablymedicinal formulation 2 are listed below. As already mentioned, they arein particular powders or liquids in the broadest sense. Particularlypreferably the formulation 2 contains the following:

The compounds listed below may be used in the device according to theinvention on their own or in combination. In the compounds mentionedbelow, W is a pharmacologically active substance and is selected (forexample) from among the betamimetics, anticholinergics, corticosteroids,PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists,H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors. Moreover,double or triple combinations of W may be combined and used in thedevice according to the invention. Combinations of W might be, forexample:

W denotes a betamimetic, combined with an anticholinergic,corticosteroid, PDE4-inhibitor, EGFR-inhibitor or LTD4-antagonist,

W denotes an anticholinergic, combined with a betamimetic,corticosteroid, PDE4-inhibitor, EGFR-inhibitor or LTD4-antagonist,

W denotes a corticosteroid, combined with a PDE4-inhibitor,EGFR-inhibitor or LTD4-antagonist

W denotes a PDE4-inhibitor, combined with an EGFR-inhibitor orLTD4-antagonist

W denotes an EGFR-inhibitor, combined with an LTD4-antagonist.

The compounds used as betamimetics are preferably compounds selectedfrom among albuterol, arformoterol, bambuterol, bitolterol, broxaterol,carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol,isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine,metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol,rimiterol, ritodrine, salmefamol, salmeterol, soterenol, sulphonterol,terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81,KUL-1248 and

-   3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide-   5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one-   4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone-   1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol-   1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol-   5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one-   1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol-   6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(ethyl    4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic    acid)-1,1-dimethyl-ethylamino]-ethyl}-   4H-benzo[1,4]oxazin-3-one-   8-{2-[1,1-dimethyl-2-(2.4.6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-   2-methyl-propyl}-phenoxy)-butyric acid-   8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol-   2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-benzaldehyde-   N-[2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide-   8-hydroxy-5-(1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinolin-2-one-   8-hydroxy-5-[1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-quinolin-2-one-   5-[2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one-   [3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea-   4-(2-{6-[2-(2.6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol-   3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzylsulphonamide-   3-(3-{7-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzylsulphonamide-   4-(2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol-   N-Adamantan-2-yl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide    optionally in the form of the racemates, enantiomers, diastereomers    thereof and optionally in the form of the pharmacologically    acceptable acid addition salts, solvates or hydrates thereof.    According to the invention the acid addition salts of the    betamimetics are preferably selected from among the hydrochloride,    hydrobromide, hydriodide, hydrosulphate, hydrophosphate,    hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,    hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,    hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

The anticholinergics used are preferably compounds selected from amongthe tiotropium salts, preferably the bromide salt, oxitropium salts,preferably the bromide salt, flutropium salts, preferably the bromidesalt, ipratropium salts, preferably the bromide salt, glycopyrroniumsalts, preferably the bromide salt, trospium salts, preferably thechloride salt, tolterodine. In the above-mentioned salts the cations arethe pharmacologically active constituents. As anions the above-mentionedsalts may preferably contain the chloride, bromide, iodide, sulphate,phosphate, methanesulphonate, nitrate, maleate, acetate, citrate,fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate,while chloride, bromide, iodide, sulphate, methanesulphonate orp-toluenesulphonate are preferred as counter-ions. Of all the salts thechlorides, bromides, iodides and methanesulphonates are particularlypreferred.

Other preferred anticholinergics are selected from among the salts offormula AC-1

wherein X⁻ denotes an anion with a single negative charge, preferably ananion selected from among the fluoride, chloride, bromide, iodide,sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate,citrate, fumarate, tartrate, oxalate, succinate, benzoate andp-toluenesulphonate, preferably an anion with a single negative charge,particularly preferably an anion selected from among the fluoride,chloride, bromide, methanesulphonate and p-toluenesulphonate,particularly preferably bromide, optionally in the form of theracemates, enantiomers or hydrates thereof. Of particular importance arethose pharmaceutical combinations which contain the enantiomers offormula AC-1-en

wherein X⁻ may have the above-mentioned meanings. Other preferredanticholinergics are selected from the salts of formula AC-2

wherein R denotes either methyl or ethyl and wherein X⁻ may have theabove-mentioned meanings. In an alternative embodiment the compound offormula AC-2 may also be present in the form of the free base AC-2-base.

Other specified compounds are:

-   tropenol 2,2-diphenylpropionate methobromide,-   scopine 2,2-diphenylpropionate methobromide,-   scopine 2-fluoro-2,2-diphenylacetate methobromide,-   tropenol 2-fluoro-2,2-diphenylacetate methobromide;-   tropenol 3,3′,4,4′-tetrafluorobenzilate methobromide,-   scopine 3,3′,4,4′-tetrafluorobenzilate methobromide,-   tropenol 4,4′-difluorobenzilate methobromide,-   scopine 4,4′-difluorobenzilate methobromide,-   tropenol 3,3′-difluorobenzilate methobromide,-   scopine 3,3′-difluorobenzilate methobromide;-   tropenol 9-hydroxy-fluorene-9-carboxylate methobromide;-   tropenol 9-fluoro-fluorene-9-carboxylate methobromide;-   scopine 9-hydroxy-fluorene-9-carboxylate methobromide;-   scopine 9-fluoro-fluorene-9-carboxylate methobromide;-   tropenol 9-methyl-fluorene-9-carboxylate methobromide;-   scopine 9-methyl-fluorene-9-carboxylate methobromide;-   cyclopropyltropine benzilate methobromide;-   cyclopropyltropine 2,2-diphenylpropionate methobromide;-   cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide;-   cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide;-   cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide;-   cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide;-   cyclopropyltropine methyl 4,4′-difluorobenzilate methobromide,-   tropenol 9-hydroxy-xanthene-9-carboxylate methobromide;-   scopine 9-hydroxy-xanthene-9-carboxylate methobromide;-   tropenol 9-methyl-xanthene-9-carboxylate-methobromide;-   scopine 9-methyl-xanthene-9-carboxylate-methobromide;-   tropenol 9-ethyl-xanthene-9-carboxylate methobromide;-   tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide;-   scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide,

The above-mentioned compounds may also be used as salts within the scopeof the present invention, wherein instead of the methobromide the saltsmetho-X are used, wherein X may have the meanings given hereinbefore forX⁻.

As corticosteroids it is preferable to use compounds selected from amongbeclomethasone, betamethasone, budesonide, butixocort, ciclesonide,deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone,loteprednol, mometasone, prednisolone, prednisone, rofleponide,triamcinolone, RPR-106541, NS-126, ST-26 and

-   (S)-fluoromethyl    6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate-   (S)-(2-oxo-tetrahydro-furan-3    S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,-   cyanomethyl    6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tertamethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carboxylate    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the salts and    derivatives thereof, the solvates and/or hydrates thereof. Any    reference to steroids includes a reference to any salts or    derivatives, hydrates or solvates thereof which may exist. Examples    of possible salts and derivatives of the steroids may be: alkali    metal salts, such as for example, sodium or potassium salts,    sulphobenzoates, phosphates, isonicotinates, acetates,    dichloroacetates, propionates, dihydrogen phosphates, palmitates,    pivalates or furoates.

PDE4-inhibitors which may be used are preferably compounds selected fromamong enprofyllin, theophyllin, roflumilast, ariflo (cilomilast),tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4418,Bay-198004, BY343, CP-325.366, D-4396 (Sch-351591), AWD-12-281(GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585,V-11294A, Cl-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and

-   N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide-   (−)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide-   (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone-   3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone-   cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic    acid]-   2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)cyclohexan-1-one-   cis[4-cyano-4-(3-cyclopropylmethoxy-4-di    fluoromethoxyphenyl)cyclohexan-1-ol]-   (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate-   (S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate-   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3.4-c]-1,2,4-triazolo[4.3-a]pyridine-   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3.4-c]-1,2,4-triazolo[4.3-a]pyridine    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the    pharmacologically acceptable acid addition salts thereof, the    solvates and/or hydrates thereof. According to the invention the    acid addition salts of the betamimetics are preferably selected from    among the hydrochloride, hydrobromide, hydriodide, hydrosulphate,    hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,    hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,    hydroxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate.

The LTD4-antagonists used are preferably compounds selected from amongmontelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001,MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and

-   1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic    acid,-   1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic    acid-   [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic    acid    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the    pharmacologically acceptable acid addition salts, solvates and/or    hydrates thereof. According to the invention the acid addition salts    of the betamimetics are preferably selected from among the    hydrochloride, hydrobromide, hydroiodide, hydrosulphate,    hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,    hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,    hydroxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate. By salts or derivatives which the    LTD4-antagonists may optionally be capable of forming are meant, for    example: alkali metal salts, such as for example, sodium or    potassium salts, alkaline earth metal salts, sulphobenzoates,    phosphates, isonicotinates, acetates, propionates, dihydrogen    phosphates, palmitates, pivalates or furoates.

EGFR-inhibitors which may be used are preferably compounds selected fromamong cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and

-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]-amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)    amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-to-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6.7-to-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinyl-carbonyl)amino]-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-   3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline-   4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-to-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-   7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1′-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N—[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-   7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline    optionally in the form of the racemates, enantiomers, diastereomers    thereof and optionally in the form of the pharmacologically    acceptable acid addition salts, solvates or hydrates thereof.    According to the invention the acid addition salts of the    betamimetics are preferably selected from among the hydrochloride,    hydrobromide, hydriodide, hydrosulphate, hydrophosphate,    hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,    hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,    hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

The dopamine agonists used are preferably compounds selected from amongbromocriptin, cabergoline, alpha-dihydroergocryptine, lisuride,pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid andviozan, optionally in the form of the racemates, enantiomers,diastereomers thereof and optionally in the form of thepharmacologically acceptable acid addition salts, solvates or hydratesthereof. According to the invention the acid addition salts of thebetamimetics are preferably selected from among the hydrochloride,hydrobromide, hydriodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

H1-Antihistamines which may be used are preferably compounds selectedfrom among epinastine, cetirizine, azelastine, fexofenadine,levocabastine, loratadine, mizolastine, ketotifen, emedastine,dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine,doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine,promethazine, ebastine, desloratidine and meclozine, optionally in theform of the racemates, enantiomers, diastereomers thereof and optionallyin the form of the pharmacologically acceptable acid addition salts,solvates or hydrates thereof. According to the invention the acidaddition salts of the betamimetics are preferably selected from amongthe hydrochloride, hydrobromide, hydriodide, hydrosulphate,hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

It is also possible to use inhalable macromolecules, as disclosed inEuropean Patent Application EP 1 003 478 A1 or Canadian PatentApplication CA 2297174 A1.

In addition, the compounds may come from the groups of ergot alkaloidderivatives, the triptans, the CGRP-inhibitors, the phosphodiesterase-Vinhibitors, optionally in the form of the racemates, enantiomers ordiastereomers thereof, optionally in the form of the pharmacologicallyacceptable acid addition salts, the solvates and/or hydrates thereof.

Examples of ergot alkaloid derivatives are dihydroergotamine andergotamine.

1. Dispensing device for dispensing a formulation as a spray, whereinthe dispensing device is adapted to receive or comprises a storagedevice with at least one or multiple, preferably separate andpre-metered doses of the formulation, wherein the dispensing devicecomprises a means for pressurizing gas, in particular air, or an airinlet for generating or allowing a gas stream flowing through thestorage device for dispensing a dose of the formulation, wherein thedispensing device is designed such that pressure pulses are generated inthe gas stream during dispensing one dose and/or the direction of gasflow alternates during dispensing one dose.
 2. Dispensing deviceaccording to claim 1, wherein the dispensing device or means forpressurizing gas comprises a connecting element for supplyingpressurized gas or air to the storage device, in particular individuallyto receptacles or storage chambers of the storage device containing thepre-metered doses of the formulation.
 3. Dispensing device according toclaim 1, wherein the connecting element is a hollow needle and/orpiercing element.
 4. Dispensing device according to claim 1, wherein themeans for pressurizing gas comprises a preferably manually operated airpump.
 5. Dispensing device according to claim 1, wherein the means forpressurizing gas comprises a bellows for compressing the gas. 6.Dispensing device according to claim 1, wherein the means forpressurizing gas comprises a spring store, in particular a spring, forcompressing the gas.
 7. Dispensing device according to claim 1, whereinthe dispensing device or storage device or means for pressurizing gascomprises a throttle for throttling the gas stream, preferably justbefore, within or after to receptacles or storage chambers of thestorage device containing the pre-metered doses of the formulation. 8.Dispensing device according to claim 2, wherein the throttle is formedby the connecting element.
 9. Dispensing device according to claim 1,wherein the dispensing device is a dry powder inhaler.
 10. Storagedevice for a dispensing device, with multiple storage members, inparticular inserts, each storage member comprising a storage cavitycontaining a dose of the formulation, and a duct for dispensing therespective dose, the duct having a smaller cross section and/or volumethan the storage chamber, wherein the duct is connected to itsassociated storage chamber via a sharp edge or transition portion. 11.Storage device according to claim 10, wherein the duct has an at leastessentially constant cross section beginning at an entry opening at aninner side wall of the storage chamber.
 12. Method for dispensing aformulation as a spray, wherein a gas stream flows through a storagedevice for dispensing a dose of the formulation, wherein pressure pulsesare generated in the gas stream during dispensing one dose and/or thatthe direction of gas flow alternates during dispensing one dose. 13.Method according to claim 12, wherein 2 to 5 pressure pulses aregenerated during dispensing one dose.
 14. Method according to claim 12,wherein the pressure of the gas stream decreases at least once by atleast 300 kPa/s during dispensing one dose.
 15. Method according toclaim 12, wherein the gas stream is generated by a bellows, which iscompressed by a spring means.
 16. Method according to claim 15, whereinthe bellows and/or spring means oscillates during dispensing one dose.